ASO Visual Abstract: Worse Survival in Co-altered RAS-TP53 Patients with Resected Colorectal Liver Metastases.

BackgroundThere have been controversial voices on if hepatitis B virus infection decreases the risk of colorectal liver metastases or not. This study aims to the find the association between HBV infection and postoperative survival of colorectal cancer and the risk of liver metastases in colorectal cancer patients.MethodsPatients who underwent curative surgical resection for colorectal cancer between January 2011 and December 2012 were included. Patients were grouped according to anti-HBc. Differences in overall survival, time to progress, and hepatic metastasis-free survival between groups and significant predictors were analyzed.ResultsThree hundred twenty-seven colorectal cancer patients were comprised of 202 anti-HBc negative cases and 125 anti-HBc positive cases, and anti-HBc positive cases were further divided into high-titer anti-HBc group (39) and low-titer anti-HBc group (86). The high-titer anti-HBc group had significantly worse overall survival (5-Yr, 65.45% vs. 80.06%; P < .001), time to progress (5-Yr, 44.26% vs. 84.73%; P < .001), and hepatic metastasis-free survival (5-Yr, 82.44% vs. 94.58%; P = .029) than the low-titer group. Multivariate model showed anti-HBc ≥ 8.8 S/CO was correlated with poor overall survival (HR, 3.510; 95% CI, 1.718–7.17; P < .001), time to progress (HR, 5.747; 95% CI, 2.789–11.842; P < .001), and hepatic metastasis-free survival (HR, 3.754; 95% CI, 1.054–13.369; P = .041) in the anti-HBc positive cases.ConclusionsHigher titer anti-HBc predicts a potential higher risk of liver metastases and a worse survival in anti-HBc positive colorectal cancer patients.

The Impact of Local and Regional Disease Extent on Overall Survival in Patients With Advanced Stage IIIB/IV Non-Small Cell Lung Carcinoma

Outcomes of Pediatric Kidney Transplantation in Recipients of a Previous Non-Renal Solid Organ Transplant.

Early adjuvant chemotherapy administration for patients with advanced stage (III-IV) malignant ovarian germ cell tumors is associated with a survival benefit (153)

BackgroundSarcopenia, as measured at the 3rd lumbar (L3) level, has been shown to prognosticate survival in cancer patients. However, many patients with early-stage non-small cell lung cancer (NSCLC) do not undergo abdominal imaging. We hypothesized that preoperative thoracic sarcopenia is associated with survival in patients undergoing lung resection for early-stage NSCLC.MethodsPatients who underwent anatomic resection for NSCLC between 2010–2019 were retrospectively identified. Exclusion criteria included induction therapy, less than 90 days of follow-up, and absence of computed tomography (CT) imaging. Cross sectional skeletal muscle area was calculated at the fifth thoracic vertebra (T5), twelfth thoracic vertebra (T12), and L3 level. Gender-specific lowest quartile values and previously defined values were used to define sarcopenia. Overall survival and disease-free survival were assessed using the Kaplan-Meier method.ResultsOverall, 221 patients met inclusion criteria with a median body mass index (BMI) of 26.5 kg/m2 [interquartile range (IQR), 23.3–29.9 kg/m2], age of 69 years (IQR, 62.4–74.9 years), and follow-up of 46.9 months (IQR, 25.0–70.7 months). At the T5 level, sarcopenic males demonstrated worse overall survival [median 41.0 (IQR, 13.8–53.7) vs. 42.0 (IQR, 23.1–55.1) months, P=0.023] and disease-free survival [median 15.8 (IQR, 8.4–30.78) vs. 34.8 (IQR, 20.1–50.5) months, P=0.007] when compared to non-sarcopenic males. There was no difference in survival between sarcopenic and non-sarcopenic females when assessed at T5. Sarcopenia at T12 or L3 was associated with worse overall survival (P<0.05).ConclusionsSarcopenia at T5 is associated with worse survival in males, but not females. When using upper thoracic vertebral levels to assess for sarcopenia, it is necessary to account for gender.

Developing sarcopenia during neoadjuvant therapy is associated with worse survival in esophageal adenocarcinoma patients

MicroRNAs are small, noncoding RNAs that regulate the expression of posttranslational genes. The presence of some specific microRNAs has been associated with increased risk of both local recurrence and metastasis and worse survival in patients with osteosarcoma. Pathologic fractures in osteosarcoma are considered to be more the manifestation of a neoplasm with a more aggressive biological behavior than the cause itself of worse prognosis. However, this has not been proved at the biological or molecular level. Currently, there has not been a microRNA profiling study of patients who have osteosarcoma with and without pathologic fractures that has described differences in terms of microRNA profiling between these two groups and their correlation with biologic behavior. (1) In patients with osteosarcoma of the extremities, how do the microRNA profiles of those with and without pathologic fractures compare? (2) What relationship do microRNAs have with local recurrence, risk of metastasis, disease-specific survival, and overall survival in osteosarcoma patients with pathologic fractures? Between 1994 and 2013, 217 patients were diagnosed and treated at our institution for osteosarcoma of the extremities. Patients were excluded if (1) they underwent oncologic resection of the osteosarcoma at an outside institution (two patients) or (2) they were diagnosed with an extraskeletal osteosarcoma (29 patients) or (3) they had less than 1 year of clinical follow-up and no oncologic outcome (local recurrence, metastasis, or death) (four patients). A total of 182 patients were eligible. Of those, 143 were high-grade osteosarcomas. After evaluation of tumor samples before chemotherapy treatment, a total of 80 consecutive samples were selected for sequencing. Demographic and clinical comparison between the sequenced and non-sequenced patients did not demonstrate any differences, confirming that both groups were comparable. Diagnostic samples from the extremities of 80 patients with high-grade extremity osteosarcomas who had not yet received chemotherapy underwent microRNA sequencing for an ongoing large-scale osteosarcoma genome profiling project at our institution. Six samples were removed after a second look by a musculoskeletal pathologist who verified cellularity and quality of samples to be sequenced, leaving a total of 74 patients. Of these, two samples were removed as they were confirmed to be pelvic tumors in a second check after sequencing. The final study sample was 72 patients (11 patients with pathologic fractures and 61 without). Sequencing data were correlated with fractures and local recurrence, risk of metastasis, disease-specific survival, and overall survival through Kaplan-Meier analyses. Several microRNAs were expressed differently between the two groups. Among the markers with the highest differential expression (edgeR and DESeq algorithms), Hsa-mIR 656-3p, hsa-miR 493-5p, and hsa-miR 381-3p were upregulated in patients with pathologic fractures, whereas hsa-miR 363, hsa-miR 885-5p, and has-miR 20b-5p were downregulated. The highest differential expression fracture and nonfracture-associated microRNA markers also distinguished groups of patients with different metastasis risk, a well as different disease-specific and overall survival. Furthermore, the profile of pathologic fractures demonstrated a higher differential expression for microRNA markers that were previously associated with a higher risk of metastasis and lower survival rates in patients with osteosarcoma. In patients who have osteosarcoma, the microRNA profiles of those with pathologic fractures are different than of patients without pathologic fractures. The highest differential expression mircroRNA molecules in patients with pathologic fractures predict also higher risk of metastatic disease as well as worse disease-specific survival and overall survival. Furthermore, we found higher differential expression of microRNAs in the pathologic fracture group previously associated with poor prognosis. The higher risk of metastasis and poorer overall survival in patients with pathologic fractures is inherent to tumor aggressive biologic behavior. It is plausible that the fracture itself is not the direct cause of worse prognosis but another manifestation of tumor biologic aggressiveness. Identification of these molecules through liquid biopsies may help to determine which patients may benefit from surgery before fractures occur. The same technology can be applied to identify patterns of response to conventional chemotherapy, assisting in more specific and accurate systemic therapy. III, prognostic study.

Background: We previously developed a liquid biopsy assay called Enhancer and neighboring loci of Androgen Receptor Sequencing (EnhanceAR-Seq) (Dang &amp; Chauhan et al, JCO PO, 2020). We applied it to a heterogeneous cohort of metastatic prostate cancer patients after the start of AR-directed therapy, and showed that alterations in the AR locus were associated with worse survival. Here we asked if AR/enhancer genomic alterations detected in plasma cell-free DNA prior to the administration of first-line AR-selective inhibitors (ARSIs) can predict survival in metastatic castration resistant prostate cancer (mCRPC) patients. Methods: We applied EnhanceAR-Seq to plasma cell-free DNA isolated from 20 mCRPC patients from Tulane University collected between April 2015 and June 2017. Assay results were correlated with patient overall survival (OS) and progression-free survival (PFS) from the time of blood collection. Results: Median follow up time was 32 months. Seventeen patients had blood plasma analyzed before first-line ARSI treatment, while three patients had received prior ARSI treatment before blood collection. EnhanceAR-Seq revealed that the most frequent genomic events detected were AR/enhancer alterations (copy number gain, tandem duplication or missense mutations) in 9 patients (45%), of which 5 patients had both AR gene body and enhancer copy number gain. The other 4 patients each had a single genomic event detected by EnhanceAR-Seq: AR amplification, AR enhancer amplification, AR and AR enhancer tandem duplication, and AR W742C single nucleotide variation. Cell-free DNA-detected alterations in the full AR locus including the AR enhancer were highly significant for inferior OS (P = 0.0009; HR = 17.0) but not for PFS (P = 0.2; HR = 2.2) by Kaplan-Meier analysis across all 20 patients. Subset analysis of the 17 patients with plasma analyzed prior to first-line ARSI treatment revealed that AR/enhancer alterations again predicted significantly worse OS with a median survival of 16.1 months vs. not-reached (P = 0.0009; HR = 14.1). Conclusions: AR locus alterations detected by EnhanceAR-seq in plasma cell-free DNA collected prior to ARSI administration correlated with significantly worse overall survival in patients with mCRPC. If corroborated, our results suggest that AR/enhancer genomic alterations represent a potent pre-treatment prognostic biomarker in mCRPC patients. Citation Format: Pradeep Singh Chauhan, Steven H. Hartman, Ha X. Dang, Jace Webster, Haley Ellis, Wenjia Feng, Peter K. Harris, Elisa M. Ledet, Ellen B. Jaeger, Patrick J. Miller, Sydney A. Caputo, Russell K. Pachynski, Oliver Sartor, Christopher A. Maher, Aadel A. Chaudhuri. Cell-free DNA alterations in the AR/enhancer locus measured before AR signaling inhibition portend poor overall survival in metastatic castration resistant prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 550.

Purpose: We aim to determine incidence and survival rates of pure vs mixed invasive lobular breast carcinoma between 1990 and 2020 in the province of Ontario, Canada. We further evaluated patient and tumour factors that predict survival for invasive lobular carcinoma (ILC). Methods: Using population-based administrative healthcare datasets at Institute of Clinical Evaluative Sciences (ICES) Ontario, we calculated the crude 5-year incidence rates of pure ILC versus invasive ductal carcinoma (IDC) versus mixed ILC-IDC in the province of Ontario, Canada between 1990 and 2020. Kaplan-Meier survival curves were generated to determine the 5-, 10-, 15- and 20-year survival for ILC (and mixed ILC-IDC) as compared with IDC. Survival curves were compared using the log-rank test and stratified by stage. Using a multivariable Cox proportional hazards regression analysis, we identified patient (e.g. demographic, geographic, socioeconomic) and tumour (grade, stage, receptor subtype) factors that predicted survival for patients with ILC. Statistical analysis was performed using SAS® and P values &amp;lt; 0.05 were considered statistically significant. Results: We identified 18,551 (8%) pure ILC, 10,234 (4%) mixed ILC-IDC and 192,371 (81%) IDC cases. The crude incidence of pure ILC increased from 55.7 per 100,000 in 1990 to 80.2 per 100,000 in 2020. The crude incidence of mixed ILC-IDC peaked in the mid-2000s at 48.6 per 100,000 and subsequently declined to 32.1 per 100,000 in 2020. There was a significant difference in overall survival between the three breast cancer subtypes. Over a 30-year follow-up period (mean 9.3 +/- 7.3 years), overall survival of mixed ILC-IDC mirrors the survival of pure IDC, while women with pure ILC have inferior survival compared with IDC beginning after 10 years of follow-up (P &amp;lt; .001). The 20-year overall survival was 40% for ILC and 50% for IDC and mixed ILC-IDC. Older age &amp;gt; 55 years (vs. 50-54 years, P &amp;lt; .0001), lowest neighborhood income quintile (HR 1.1, P = .038), geographic location within Ontario (P &amp;lt; .01) and increasing Elixhauser Comorbidity Index score (P &amp;lt; .0001) predicted worse overall survival for ILC patients. Conversely, the increasing number of mammograms received in the five years prior to diagnosis predicted better overall survival (P &amp;lt; .0001). When stratified by cancer stage, the worse survival in ILC (compared with IDC and mixed ILC-IDC) was only observed for stage III patients (P = .01). Stage III and IV disease, grade 3 histology and ER/PR negativity predicted worse survival (P &amp;lt; .01). Conclusion: The crude incidence of ILC is increasing over time. Over a 30-year follow-up period (mean 9.3 +/- 7.3 years), ILC had worse overall survival compared with IDC and mixed ILC-IDC, particular stage III patients. Patient demographic and tumour factors predict overall survival in ILC. While treatment paradigms for ILC mirror that for IDC, our data demonstrates worse overall survival for ILC and a need for more research and treatments focused on improving long-term survival for ILC patients. Citation Format: David Lim, Vasily Giannakeas, Steven Narod, Kelly Metcalfe. Population-based survival outcomes of pure vs mixed invasive lobular breast carcinoma in Ontario, Canada [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-11.

Different independent associations of depression and anxiety with survival in patients with cancer

Abstracts and Case Studies for the College of American Pathologists 2021 (CAP21) Annual Meeting

To examine genomic correlates of conversion to resection (CTR and overall survival (OS) in patients with initially unresectable colorectal liver metastasis (IU-CRLM) treated with combination systemic and hepatic artery infusion (HAI) chemotherapy. In patients presenting with IU-CRLM, combination systemic and HAI chemotherapy enables CTR with associated long-term OS in a subset of patients. Genomic correlates of CTR and OS in IU-CRLM have not been previously explored. Specimens from IU-CRLM patients receiving systemic/HAI chemotherapy (2003-2017) were submitted for next-generation sequencing. Fisher Exact test assessed associations with CTR, and Kaplan-Meier/Cox methods assessed associations with OS from HAI initiation. Of 128 IU-CRLM patients, 51 (40%) underwent CTR at median 6 months (range: 3-35) from HAI initiation. CTR and persistently unresectable cohorts differed significantly in preoperative systemic chemotherapy exposure, node-positive primary status, and size of largest liver metastasis. Median and 5-year OS was 66 months and 51%. CTR was associated with prolonged survival (time-dependent HR 0.23,95% CI: 0.12-0.46, P < 0.001). The most frequently altered genes were APC (81%), TP53 (77%), and KRAS (37%). Oncogenic mutations in SOX9 and BRAF were associated with CTR. BRAF mutations, any RAS pathway alterations, and co-altered RAS/RAF-TP53 mutations wereassociated with worse survival. Classification and regression tree analysis defined prognostically relevant clusters of genomic risk to reveal co-altered RAS/RAF-TP53 as the highest risk subgroup. Co-altered RAS/RAF-TP53 remained independently associated with worse survival (HR 2.52, 95% CI: 1.37-4.64, P = 0.003) after controlling for CTR, number of liver metastases, and preoperative extrahepatic disease. Distinct genomic profiles are associated with CTR and survival in patients with IU-CRLM treated with HAI/systemic chemotherapy. Presence of SOX9, BRAF , and co-altered RAS/RAF- TP53 mutations are promising biomarkers that, when validated in larger datasets, may impact treatment of IU-CRLM patients.

Pancreatic Cancer has a 12% 5-year survival rate due to late-stage detection and lack of many chemotherapy or targeted therapy options. TIGIT is an immune checkpoint inhibitor being explored in clinical trials in pancreatic cancer due to the implications of its ligand (CD155) promoting immune evasion. TIGIT is a marker of T cell exhaustion and plays a key role in the inhibition of anti-tumor immune responses. We hypothesize that targeted anti-TIGIT therapy, in conjunction with other therapies targeting the tumor microenvironment, could reverse immune suppression that is characteristic of pancreatic ductal adenocarcinoma (PDAC). As such, here we aim to quantify TIGIT expression using automated RNAscope technology and to correlate it with overall patient survival. We performed RNAscope in situ hybridization and immunohistochemistry on 25 primary and 4 metastatic (liver) formalin-fixed paraffin-embedded (FFPE) tissue sections from patients with histologically confirmed PDAC. A nuclear counterstain combined with an RNAscope probe specific for the human TIGIT mRNA was utilized. Slides were scanned at 40X magnification with an automated slide scanner and quantified using the ISH-IHC module of the HALO-v3.5 software. After cells were segmented based on nuclear recognition, the presence of TIGIT probe within the cytoplasm of each cell was determined and quantified. Percent positive cell values were then exported for statistical analysis in SPSS. De-identified clinical metadata was obtained from REDCap, a cloud-based HIPAA-compliant database used to compile patient data for research purposes. Gender, survival months, ethnicity, race, tumor histology, stage, cancer history, treatment status, and comorbidities were evaluated. We analyzed a cohort of 29 histologically-confirmed surgically resected PDACs, comprised of 25 primary pancreatic tumor samples and 4 metastatic liver core biopsies. The mean percentage of TIGIT positive cells was 63%. From this, the TIGIT high versus low threshold was determined to be 70%. High TIGIT was associated with significantly lower overall survival (p=.013), suggesting that expression of TIGIT and T cell exhaustion may predict overall worse survival. The median overall survival months for the TIGIT low group was 321 months versus 106 months for the TIGIT high group. This data leads us to hypothesize that expression of TIGIT and T cell exhaustion may predict worse overall survival. Anti-TIGIT medications are currently in clinical trials for metastatic PDAC. Here we demonstrate that high TIGIT expression is associated with an overall worse prognosis and present a novel, automated TIGIT detection protocol that may be used to determine if patients are candidates for anti-TIGIT therapy. In a clinical setting, this novel, automated biomarker TIGIT detection protocol could be used to select candidates for anti-TIGIT therapy. This may lead to improved overall patient survival. Citation Format: Madison George, Julie Clark, Kendyll Gartrelle, Georges Nassif, Donald Rempinski, Daniel Long, Hui-Ju Wen, Simone Benitz, Samuel Zwernik, Rupen Shah, Hakmin Park, David Kwon, Philip Philip, Gazala Khan, Howard Crawford, Brian Theisen, Nina Steele. TIGIT expression correlates to worse overall survival in primary and metastatic pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C012.

Next-generation sequencing provides valuable information about mutations within colorectal liver metastases (CRLMs) that impact survival. Existing data focus on prognostic implications of single gene mutations. This study assessed the impact of co-alterations on KRAS/NRAS and TP53 after CRLM resection. A retrospective analysis was performed for patients with CRLM who underwent surgical management and had next-generation sequencing (NGS) performed to assess associations with clinical outcomes. Groups were stratified by the presence or absence of RAS-TP53 co-alterations (RTC). The study cohort consisted of 155 patients with NGS data, with 42 patients (27%) harboring RTC. The baseline characteristics were similar between the groups. The RTC patients had more right-side primary tumors (45% vs. 26%; P = 0.028), presented more frequently with synchronous CRLM (91% vs. 72%; P = 0.017), and were more often deemed initially unresectable (26% vs. 12%; P = 0.038). Medical and surgical management were comparable between the groups, with the majority of the patients receiving systemic therapy (97% overall) and undergoing wedge partial hepatectomies (59% overall). The RTC patients had worse recurrence-free and overall survival, and experienced extrahepatic recurrences sooner (median, 9 vs 14 months; P = 0.014). In the multivariate analyses, RTC (hazard ratio [HR, 2.076; 95% confidence interval [CI], 1.054-4.088; P = 0.035) and post-recurrence locoregional treatments (HR, 0.446; 95% CI 0.222-0.896; P = 0.023) were independently associated with survival. The RTC patients presented more often with synchronous CRLM, and RTC also was associated with worse oncologic outcomes, suggestive of more aggressive tumor biology. Integration of genome-sequencing data beyond single gene mutations may provide important prognostic information for patients with CRLM to guide management decisions.

Patients with a history of diabetes mellitus (DM) have worse survival than those without DM after liver transplantation. However, the effect of liver grafts from DM donors on the post-transplantation survival of recipients is unclear. Using the Scientific Registry of Transplant Recipients database (2004–2008), 25,413 patients were assessed. Among them, 2,469 recipients received grafts from donors with DM. The demographics and outcome of patients were assessed. Patient survival was assessed using Kaplan–Meier methodology and Cox regression analyses. Recipients from DM donors experienced worse graft survival than recipients from non-DM donors (one-year survival: 81% versus 85%, and five-year survival: 67% versus 74%, P<0.001, respectively). Graft survival was significantly lower for recipients from DM donors with DM duration >5 years (P<0.001) compared with those with DM duration <5 years. Cox regression analyses showed that DM donors were independently associated with worse graft survival (hazard ratio, 1.11; 95% confidence interval, 1.02–1.19). The effect of DM donors was more pronounced on certain underlying liver diseases of recipients. Increases in the risk of graft loss were noted among recipients from DM donors with hepatitis-C virus (HCV) infection, whereas those without HCV experienced similar outcomes compared with recipients from non-DM donors. These data suggest that recipients from DM donors experience significantly worse patient survival after liver transplantation. However, in patients without HCV infection, using DM donors was not independently associated with worse post-transplantation graft survival. Matching these DM donors to recipients without HCV may be safe.